(benzimidazol-2-ylthio)-benzoyl-alkyl carboxylic acids and their alkyl esters

ABSTRACT

WHEREIN   THIAZOLO(3,2-A)BENZIMIDAZOLE   2-(R2-OOC-(CH2)N-),3-HO,3-(R3-C6H4-),R1-2,3-DIHYDRO-   2-(R3-C6H4-CO-CH(-(CH2)N-COO-R2)-S-),R1-BENZIMIDAZOLE, OR   R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, (LOWER)ALKYL, TRIFLUOROMETHYL, NITRO AND AMINO; R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND (LOWER)ALKYL; R3 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGERN, (LOWER)ALKYL, TRIFLUOROMETHYL, NITRO, AMINO, PHENYL, HALOPENYL AND (LOWER)ALKYLPHENYL; N IS AN INTEGER OF FROM 1 TO ABOUT 3; AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. NOVEL COMPOUNDS OF FORMULA I AND FORMULA II HAVE BEEN PREPARED WHICH HAVE CNS DEPRESSANT AND ANTITUBERCULAR ACTIVITY:

United States Patent (BENZAZOL 2 YLTHIO)-BENZOYL-ALKYL CARBOXYLIC ACIDSAND THEIR ALKYL ESTERS Peter H. L. Wei, Springfield, and Stanley C.Bell, Penn Valley, Pa., assignors to American Home Products Corporation,New York, NY.

No Drawing. Original application Mar. 17, 1971, Ser. No. 125,378, nowPatent No. 3,704,239. Divided and this application July 20, 1972, Ser.No. 273,570

Int. Cl. (107d 49/38 U.S. Cl. 260-3092 6 Claims ABSTRACT OF THEDISCLOSURE Novel compounds of Formula I and Formula II have beenprepared which have CNS depressant and antitubercular activity:

wherein R is selected from the group consisting of hydrogen, halogen,(lower)alkyl, trifluoromethyl, nitro and amino;

R is selected from the group consisting of hydrogen and (lower) alkyl;

R is selected from the group consisting of hydrogen, halogen,(lower)alkyl, trifluoromethyl, nitro, amino, phenyl, halophenyl and(lower)alkylphenyl;

n is an integer of from 1 to about 3; and the pharmaceuticallyacceptable acid addition salts thereof.

This is a division, of application Ser. No. 125,378, filed Mar. 17,1971, now US. 3,704,239.

DESCRIPTION OF THE INVENTION This invention is directed to thepreparation of new and novel pharmacologically active compounds. Thecompounds of the invention are those of Formulas I and H.

/ /N\ 2)n 2 2 N\\/S (ca kco a 1 NH Rig-N 0H l QR s (I) (II) wherein R isselected from the group consisting of hydrogen, halogen, (lower)alkyl,trifluoromethyl, nitro and amino;

R is selected from the group consisting of hydrogen,

and (lower)alkyl;

R is selected from the group consisting of hydrogen, halogen,(lower)alkyl, trifluoromethyl, nitro, amino phenyl, halophenyl and(lower)alkylpheny1;

n is an integer of from 1 to about 3; and the pharmaceuticallyacceptable acid addition salts thereof.

The following reaction scheme illustrates the process 3,775,426 PatentedNov. 27, 1973 ice YSE R NH reflux in H 0 or a (III) (I A to fydrolysiewherein R R and n are the same as hereinabove described; R, is(lower)alky1 and X is halogen.

In the above described procedure when the compounds are directlycyclized, glacial acetic acid, dimethoxy ethane or a correspondingalcohol may be employed as a solvent. It is preferred to heat thereactants at a temperature of from 80 to.100 for a period of from aboutthree to about fifteen hours. The crude product may then berecrystallized from a suitable solvent such as acetone or acetonitrile.When the compounds of Formulas III and IV are admixed, it is preferredto employ an alcohol wherein R of Formula IV is the same as R, of thealcohol as the solvent. The reacants are then refluxed for a period ofabout five to fifteen hours. The product may be separated byconventional techniques purified by recrystallization. Compounds ofFormula VI may be hydrolyzed to compounds of Formula VII by conventionaltechniques. The term weak base as employed herein is meant to includesodium bicarbonate, sodium carbonate,

potassium carbonate, pyridine, triethylamine and the like. Compoundswherein R is hydrogen may also be prepared as follows:

VIII

dimechoxy ethane V A 80 to 100 l S (CH 2110023 3 l\ 0H wherein R R and Xare the same as hereinabove described.

In the above-described reaction scheme, it is preferred to heat thecompounds of Formulas III and VIII for a period of from about five toabout fifteen hours. The crude hydrohalide salts of Formula VII may thenbe purified by recrystallization from a suitable solvent. Thecyclization of Formula V to Formula VI may be ac complished by theaddition of water or a weak base.

The compounds of Formula I and Formula II were R is lower alkyl, whilenot being limited thereto, are useful for the in vitro inhibition of M.tuberculosis. The compounds thus may be employed for example inhospitals, sanitariums and the like to effectively inhibit the causativeorganisms of tuberculosis by contacting infected areas and materialswith aqueous dispersions of said compounds. Where R of the compounds ofFormula I and Formula II is hydrogen, the compounds are central nervoussystem depressants. Compounds of the invention have been tested bydetermining the minimal inhibitory concentration which will completelyinhibit M. tuberculosis, human type, strain H37Rv. The compounds ofFormulas I and II, wherein R is lower alkyl, have been found to beactive when admixed with the test organism in an aqueous dispersion at aconcentration of 50 ug/ml. Some compounds such as 3-(pchlorophenyl) 2,3dihydro 3-hydroxythiazolo[3,2-a] benzimidazole-Z-acetic acid, ethylester, have been found to be effective at a concentration of 0.5,ug./ml.

In the evaluation of the biological activity of the compounds ofFormulas I and II wherein R is hydrogen, the in vivo effects were testedas follows: The compound was administered orally or intraperitoneally tothree mice (14 to 24 grams) at each of the following doses: 400, 127, 40and 12.7 milligrams per kilogram of host body weight (mpk.). The animalswere watched for a minimum of two hours during which time signs ofgeneral stimulation, (i.e., increased spontaneous motor activity,hyperactivity on tactile stimulation; twitching), general depression(i.e., decreased spontaneous motor activity, decreased respiration)autonomic activity (i.e., miosis, mydriosis, diarrhea) were noted.

The compounds of this invention induce central nervous system depre santeffects at a dose of 40 to 400 mpk. intraperitoneally. Thus thecompounds of Formulas I and II wherein R is hydrogen, have demonstratedutility as pharmacologically active compounds in experimental andcomparative pharmacology and are of value in the treatment of mammals,e.g., mice, rats, etc., who are responsive to treatment with centralnervous system depressant agent Specifically the compounds may beadministered for the purpose of inducing a calming effect in mammals.

The nomenclature employed to described certain substituted compounds ofFormula I uses a parenthetical numbering system, e.g. 5(6) or 4(7), toidentify the positioning of substituents on the benzimidazolyl moiety.The reason for this type of nomenclature is because it is not possibleto fix the position of the substituent because of the proton shift dueto the -NHC=N group. This is in accordance with the nomenclature forimidazole type compounds set forth in Heterocyclic Compounds, R. C.Elderfield, Editor, vol. 5, pp. 198, 199 and 238. To decribe thecompounds of Formula II when the benzimidazolyl moiety is substituted,the alternative nomenclature is employed. This is because when thecompounds of Formula II are formed by ring closure the tautomerism ofthe NHC=N moiety does not permit any absolute prediction as to thepositioning of the benzimidazolyl moiety.

EXAMPLE 1 3 (benzimidazol 2 ylthio)-3-(p-chlorobenzoyl)propionic acid,ethyl ester, hydrobromide An alcoholic solution of ethyl ester3-bromo-3-(p-chlorobenzoyl)propionic acid (16.0 g., 0.05 m.) and2-merceptobenzimidazole (7.5 g., 0.05 m.) was heated on a steam bath for5 hours. After the solvent was removed the residue was dissolved inbenzene. The solid was collected and weighed 21.8 g. The crude materialwas recrystallized from ethanol. The pure ethyl ester of3-(benzimidazole-2- ylthio) 3 (p chlorobenzoyl) propionic acidhydrobromide had a melting point of 168170 C.

Analysis.-Calcd. for C19H17C1N2O3S'HBI' (percent): C, 48.57; H, 3.86; N,5.98. Found (percent): C, 48.23; H, 4.09; N, 6.07. IR spectrum showed atwin carbonyl ester 5.75u and keto 5.90 1. The NMR spectrum showedaromatic protons at 7.86 (m.); methane at 5.96 (t.); acetyl methylene at3.36; ethoxy at 4.1 (q.) and 1.26 (t.) and also exchangeable proton at9.66.

EXAMPLE 2 3 (p chlorophenyl 2,3 dihydro-3-hydroxythiazolo-[3,2-a]benzimidazole-Z-acetic acid, ethyl ester The hydrobromide of theethyl ester 3-(benzimidazole- 2-ylthio)-3-(p-chlorobenzoyl)propionicacid, (21.8 g.) was first ground and then added to 500 ml. of water. Thesuspension was stirred at room temperature for five hours. The solid wascollected and rinsed with water and sucked dry. Recrystallization of thecrude material from acetone, gave 15 g. of pure ethyl ester of3-(p-chlorophenyl)-2,3- dihydro 3 hydroxythiazole[3,2-a]benzimidazoleacetic acid, M.P. -2 C.

Analysis.-Calcd. for C19H1'7C1N203S (percent): C, 58.68; H, 4.41; N,7.21. Found (percent): C, 58.70; H, 4.44; N, 7.07. IR spectrum showedthe absence of amine salt absorption at 3.61.1. and keto signal at5.9,!L- The NMR spectrum: aromatic 7.56(m.); methine 5.86 (two sets ofdoublets); acetyl methylene 3.36; ethoxy 4.16 (q.) and 1.26 (t.).

EXAMPLE 3 3 (p chlorophenyl 2,3 dihydro-3-hydroxythiazolo-[3,2-a]benzimidazole-Z-acetic acid A dimethoxyethane solution ofZ-mercaptobenzimid a'zole (10.0 g., 0.066 m.) and3-bromo-3-(p-chlorobenzoyl)propionic acid (17.4 g., 0.06 m.) was heatedfor 3 hours. The solid that separated from the chilled solution wascollected, washed with dimethoxyethane, and dried to give 25 g. of crudehydrobromide salt of 3-(p-chlorophenyl) 2,3 dihydro 3hydroxythiazolo[3,2-a]benzimidazole-Z-acetic acid, M.P. 203-205. The IRspectrum of the hydrobromide of the thiazoloberlzirnidazole acetic acidshowed only a single free carboxylic function at 6.0

The above hydrobromide salt (17 g.) dissociated in water to give thefree acid, which was recrystallized from acetonitrile to give 12.0 g. ofpure 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2-a]benzimidaz0le-2 acetic acid, M.P. -3.

Analysis.Calcd. for C H ClN O S (percent): C, 56.59; H, 3.63; N, 7.76;S, 8.89. Found (percent): C, 56.33; H, 3.58; N, 7.47; S, 9.12.

The acid was also obtained by alkaline hydrolysis of the correspondingester followed by neutralization.

The hydrobromide of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazole[3,2-a]benzimidazole-Z-acetic acid was also prepared byheating a glacial acetic acid solution of 3-bromo-3-(p-chlorobenzoyl)propionic acid (11.64 g., 0.04 m.) and Z-mercaptobenzimidazole (6.00 g.,0.04 m.) on a steam bath for 3 /2 hours. The crude solid weighed 15 g.

EMMPLE 4 3 (p chlorobenzoyl) 3 (benzimidazole-Z-ylthio) propionic acid,methyl ester, hydrobromide 3 bromo 3 (p-chlorobenzoyl)propionic acid(60.0 g.) dissolved in methanol was heated to reflux for two days. Thesolvent was removed, and the residue dissolved in benzene. The benzenesolution was washed with sodium bicarbonate and then dried overanhydrous magnesium sulfate. After the benzene was removed, a heavy oil(64 g.) was obtained. The IR spectrum: ester 5.75;t; O=O 5.9;t. NMR:aromatic 8.06 (m.); methine 5.66 (two sets of doublets); OCH 3.76 (s.);methylene 3.36 (two sets of quartets).

The methyl ester was also prepared by methylation of the correspondingacid with diazomethane.

A methanol solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid,methyl ester (6.1 g., 0.02 m.) and 2-mercaptobenzimidazole (3.0 g., 0.02m.) was heated to reflux for six hours. After filtration the solutionwas concentrated. The oily residue was treated with benzene and thesolid was collected. The crude material was recrystallized from amixture of methanol and acetone to give 4.5 g. of pure material, M.P.182-5 Analysis.--Calcd. for C H ClN O S-Hll3r (percent): C, 47.42; H,3.54; Br, 17.53; Cl, 7.78; N, 6.15; S, 7.03. Found (percent): C, 47.32;H, 3.64; Br, 17.72; Cl, 7.86; N, 6.25; S, 7.03. IR (KBr): amine HBr3.6;t; ester 5.811,; C=O 6.0;t. NMR: aromatic 7.66; methine 6.46:methylene and OCH 3.76.

EXAMPLE 5 3-(benzimidazol-2 ylthio) 3 benzoylpropionic acid, ethylester, hydrobromide The 3-benzoylpropionic acid was esterified inabsolute ethanol in the presence of HCl. The ester was brominated inchloroform to give 3-bromo-3-benzoylpropionic acid, ethyl ester which isan oil. IR: C-H 3.4;t; ester 5.75 C=O 5.9 NMR: aromatic 7.66 (m.);methine 5.56 (two sets of doublets); methylene 3.256 (two sets ofquartets); ethoxy 4.16 (q.) and 1.26 (t.).

An ethanol solution of 3-bromo-3-benzoylpropionic acid, ethyl ester(14.25 g., 0.05 m) and Z-mercaptobenzimidazole (7.5 g., 0.05 In) washeated to reflux for six hours. After filtration the solution wasconcentrated. The residue upon treatment with 50 ml. acetone gave somesolid which was collected. The crude material was recrystallized fromacetone. The pure material weighed 14.5 g. and had a melting point of126-7".

AnaZysis.-Calcd. for C H N O S-HBr (percent): C, 52.42; H, 4.40; Br,18.35; N, 6.44; S, 7.37. Found (percent): C, 52.46; H, 4.28; Br, 18.08;N, 6.39; S, 7.43. IR: 3.6;; amine HBr; ester 5.7.[L; C=O 5.9;t. NMR:aromatic 7.56 (m.); methine 5.96; methylene 3.26; ethoxy 4.06 (q.) and1.16 (t.).

EXAMPLE 6 2,3-dihydro-3-hydroxy-3-phenylthiazolo[3,2-a]benzimidazole-Z-acetic acid, ethyl ester A benzene-water mixture of3-(benzimidazol-2-ylthio)-3-benzoylpropionic acid, ethyl ester, hydrobromide, (9.0 g.) was stirred and neutralized with a dilute NaHCO solution.The layers were separated. The organic layer was dried over anhydrousmagnesium sulfate. After benzene was removed, the residue was treatedwith acetone and the solid (7.0 g.) was collected. The crude materialwas recrystallized from acetone to give pure compound, M.P. 129-31.

Analysisr-Calcd. for C H N O S (percent): C, 64.39; H, 5.12; N, 7.91; S,9.05. Found (percent): C, 64.31; H, 5.18; N, 7.63; S, 9.08. IR: 0H3.2;t; ester 5.75;t. NMR: aromatic 7.46 (m.); methine 5.66; methylene3.26; ethoxy 4.16 (q.) and 1.26 (t.).

EXAMPLE 7 2,3 dihydro-3-hydroxy 3phenylthiazolo[3,2-a]benzimidazole-Z-acetic acid, methyl ester,hydrobromide 3 benzoylpropionic acid (100 g.) was esterified with methylalcohol which was saturated down HCl. After the solution was heated toreflux overnight, the solvent was removed. The residue was dissolved inbenzene, and the benzene solution was washed with a dilute NaHCOsolution and dried over anhydrous MgSO After removal of benzene therewas obtained g. of 3-benzoylpropionic acid, methyl ester. IR: ester,5.75 keto, 9.0M.

The above keto ester was brominated in a chloroform solution was 79 g.of bromine. The 3-bromine-3- benzoylpropionic acid, methyl ester (134g.) was an oil. IR: ester, 5.75;t; keto 9.0;t. NMR (CD01 aromatic. 7.76(m.); methine, 5.56 (two sets of doublets); acetylmethyl, 3.66 (two setsof quartets); CH O, 3.76 (s.).

(A) A glacial acetic acid solution of Z-mercaptobenzimidazole (2.5 g.,0.0166 in) and 3-bromo-3-benzoylpropionic acid, methyl ester (4.5 g.,0.02 m) was heated on a steam bath for one hour. After the solvent wasremoved, the residue was first washed with anhydrous ether and thendissolved with a small amount of acetone. The crude solid material (3.1g.) which separated out from acetone was collected and recrystallizedfrom the same solvent to give pure compound, M.P. 7.

Analysis.Calcd. for C H N O S-HBr (percent): C, 51.31; H, 4.07; Br,18.97; N, 6.65; S, 7.61. Found (percent): C, 51.60; H, 4.28; Br, 19.05;N, 6.69; S, 7.84. IR: OH, 3.25;; amine H Br, 4.0;t; ester, 5.85m NMR(DMSO): aromatic, 7.56 (m.); methine, 5.96 (t.); methylene, 3.36 (twosinglets); OCH 3.66 (s.); exchangeable, 12.16.

(B) 2,3 dihydro-3-hydroxy 3 phenylthiazolo[3,2-a] benzimidazole-Z-aceticacid, methyl ester, hydrobromide was also prepared by heating to refluxa methanol solution of 3-bromo-3-benzoylpropionic acid, methyl ester(10.8 g., 0.04 m) and 2-mercaptobenzimidazole (6.0 g., 0.04 m) for fivehours. The crude material (13.5 g.), after removal of solvent, wasrecrystallized from acetonitrile EXAMPLE 8 3 [5-(6-aminobenzimidazol-2-ylthio] -3 -(p-chlorobenzoyl) propionic acid,ethyl ester, hydrobromide An ethanol solution of3-bromo-3-(p-chlorobenzoyl) propionic acid, ethyl ester (12.8 g., 0.04m) and S-amino- Z-benzimidazolethiol (6.6 g., 0.04 m) was heated toreflux for 3% hours. After the solution was treated with Darco, thesolvent was removed. The oily residue was treated with benzene to give16 g. of crude material. The crude material was recrystallized from amixture of C H OH and acetone, dec. at 250.

Analysis.-Calcd. for C19H13C1NO3S":HBI' (percent): C, 47.18; H, 3.75;Br, 16.52; Cl, 7.33; N, 8.69; S, 6.63. Found (percent): C, 46.83; H,3.90; Br, 16.00; Cl, 7.10; N, 8.63; S, 7.02. IR: amine HBr, 3.5;t;ester, 5.7;t; ketone, 5. 85 NMR (DMSO): aromatic 7.686 (m.); methine,5.96; methylene, 3.36; ethoxy, 4.16 (q.) and 1.16 (t.), alsoexchangeable at 10.06.

EXAMPLE 9 3-(p-chlorophenyl-Z,3-dihydro-3-hydroxythiazolo-[3,2-a]benzimidazole-Z-acetic acid, methyl ester A suspension of3-(p-chlorobenzoyl)-3-(benzimidazol- 2-ylthio)propionic acid, methylester, hydrobromide (12.0 g.) in a mixture of chloroform and water wasstirred and neutralized with a dilute solution of NaHCO The layers wereseparated. The chloroform layer was washed once with water and driedover anhydrous MgSO After removal of the solvent, the oily residue wasdissolved in acetone. From the acetone solution 8.2 g. of the product(M.P. 132-4) was obtained.

Analysis.-Calcd. for C H ClN O S (percent): C, 57.68; H, 4.03; Cl, 9.46;N, 7.48; S, 8.56.. Found (percent): C, 57.20; H, 3.98; CI, 9.27; N,7.32; S, 8.73. IR: OH, 3.3;t; ester, 5.75;/.. NMR (DMSO); aromatic, 7.56(m.); methine, 5.86; OCH 3.66 (s.); methylene, 3.36.

EXAMPLE 10 3- (p-chlorobenzoyl) -3- [5 (6) -nitrobenzimidazol-2-y1thio]propionic acid, ethyl ester, hydrobromide A glacial acetic acidsolution of 3-bromo-3-(p-chlorobenzoyl)propionic acid, ethyl ester (12.7g., 0.04 m) and 7 5-nitro-2-benzimidazolethiol (7.8 g., 0.04 m) washeated on a steam bath for 15 hours. The yellow solid was collected. Themother liquor upon concentration gave more solid. The crude material wasrecrystallized from ethanol.- The pure product weighed 13 g. and meltedat 218-20".

Analysis.-Calcd. for C H ClN O S-HBr (percent): c, 44.32; H, 3.33; Br,15.52; (:1, 6.89; N, 8.16; s, 6.23. Found (percent): C, 44.38; H, 3.32;Br, 15.18; Cl, 6.74; N, 7.81; S, 5.98. The IR spectrum showedabsorptions for ester at 5.8; keto group at 6.0 N group at 6.7 and 7.5The NMR spectrum (DMSO-d showed aromatic protons at 8.16 (m.), a methineproton at 6.16 (t.), two methylene protons at 4.26 (q.), two methyleneprotons at 3.38, there methyl protons at 1.26 a triplet exchangeableproton at 9.85.

EXAMPLE 1 1 3-(p-chlorophenyl) 2,3 dihydro-3-hydroxy-7-(or 6)-nitrothiazolo[3,2-a]benzimidazole-Z-acetic acid, ethyl ester,hydrobromide A mixture of 3-(p-chlorobenzoyl-3-[S-(or6)-nitrobenzimidazol-Z-ylthio]-propionic acid, ethyl ester hydrobromide(9.0 g.) in chloroform and a dilute sodium bicarbonate solution wasstirred at room temperature for two hours. A small amount of solid wasfiltered off. The layers were separated. The chloroform layer was washedwith water and dried over anhydrous magnesium sulfate. After chloroformwas removed, the residue was treated with benzene and the solid wascollected. The crude material weighing 7.2 g. was recrystallized frombenzene and the pure compound melted at 9910l.

AnaIysis.-Calcd. for C H ClN O S (percent): C, 52.59; H, 3.72; Cl, 8.17;N, 9.69; S, 7.39. Found (percent): C, 52.51; H, 3.66; Cl, 8.64; N, 9.74;S, 7.36. The IR spectrum showed absorption for ester 5.75;, nitro groupat 6.55 and 7.5

EXAMPLE 12 W-s-Tnorrmoom,

wherein R R R and n are defined below:

5 (6) amino Ethyl 2 4 (7) methyl n-Propyl -b omo 1 5 (6) chloro...Hydrogen 3 5(6) bromo eth 2 4 (7) lodo Hydrogen 2 5 (G) fluoro thyl-.. 35 (6) ethyl Hydrogen 3-amin0-.. 2 5 (6) n-propyl ethyl 4-nitro 1 4 (7)methyl dn Phenyl 1 4 (7) chloro Ethyl p-Tolyl. 2 5 (6) hydrogen Methylp-Ohlorophenyl 1 5 (6) trifluoromethyl Ethyl 4-fiuorn 3 5 (6) hydrogenHydrogen 4-eth 3 D0 Hydrogen m-Bromophenyl 2 EXAMPLE 13 By methodsanalogous to those employed above the following compounds are prepared:

wherein R R R and n are defined below:

6 or 7 amino. Ethyl it-methyl 5 or 8 methyl-..

6 or 7 chloro.

Do 6 or 7 ethyl- 6 or 7 n-propyl 6 or 7 tnlluorometliyl 6 or 7 hydrogen3-n-propyl p-Chlorophenyl m-Bromophenyl wwwwwv-norowwroreceww 3 .5...tag;

wherein R is selected from the group consisting of hydrogen, halogen,(lower)alky1, trifiuoromethyl, nitro and amino; R is selected from thegroup consisting of hydrogen and lower alkyl; R is selected from thegroup consisting of hydrogen, halogen, (lower alkyl, trifluoromethyl,nitro, amino, phenyl, halophenyl and (lower) alkylphenyl; n is aninterger of from 1 to 3; and the pharmaceutically acceptable acidaddition salts thereof.

2. A compound as defined in claim 1 which is 3-(benzimidabol-2-ylthio)-3(p-chlorobenzoyl)propionic acid, ethyl ester, hydrobromide.

3. A compound as defined in claim 1 which is 3-(p chlorobenzoyl) -3-(benzimidazole-Z-ylthio propionic acid, methyl ester, hydrobromide.

4. A compound as defined in claim 1 which is3-(benzimidazol-Z-ylthio)-3-benzoylpropionic acid, ethyl ester hy-,drobromide.

5. A compound as defined in claim 1 which is 3-[5(6)-aminobenzimidazol-Z ylthioJ-3-(p chlorobenzoyl)propionic acid, etheylester, hydrobromide.

6. A compound as defined in claim 1 which is 3-(pchlorobenzoyl)-3-[5(6)nitrobenzimidazol 2-ylthio]- propionic acid, ethyl ester, hydrobromide.

OTHER REFERENCES C.A. 51:9814i (1957) Rebstock et a1.

HENRY R. JILES, Primary Examiner S. D. WINTERS, Assistant Examiner

